Neuropathic pain is often associated with peripheral nerve injury, (e.g. sciatic nerve) caused by compression, transection, and/or inflammation (FIG. 1) [34]. When injured or inflamed tissue persists chronically, this leads to ongoing excitation in primary sensory pain neurons located in the dorsal root ganglia (DRG) that communicate to pain transmission neurons in the dorsal horn of the spinal cord. Injured or inflamed tissue in the central nervous system can alter and excessively activate spinal pain transmission neurons in the pain pathway. If these events continue, chronic pain ensues. Pathological pain occurs when abnormal sensory processing occurs in the pain pathway such that non-painful light mechanical touch can become encoded as painful (allodynia). Chronic neuropathic pain (>3 months) is thus no longer the adaptive, protective mechanism that normal pain serves for recuperation and wound healing [19].
Glial (astrocytes, microglia, satellite & Schwann) cells are recognized as contributing to the development and maintenance of neuropathic pain [86]. Glia are well-known to serve a number of housekeeping functions for healthy neuronal communication. However, a number of animal models, including peripheral nerve inflammation and trauma, demonstrate spinal cord glial (astrocytes & microglia) activation is a common underlying mechanism that leads to pathological pain [97]. Glia have receptors for and are activated by invading pathogens, neuropeptides and neurotransmitters [97]. Once activated, glia can contribute to persistent pathological pain by responding to and releasing factors that act on both neurons and surrounding glia. Classic immune signals include the pro-inflammatory cytokines, interleukin-1 (IL-1β) and tumor necrosis factor-alpha (TNF-α), and chemokines such as CCL2 [139, 142]. Chronic constriction injury (CCI) is a well-characterized animal model that involves both inflammation and trauma around one sciatic nerve. Loose sciatic nerve ligation of 4 sutures produces allodynia in hind paws of rodents. Allodynia in rodents is often measured by hind paw responses to low threshold mechanical stimuli (von Frey test). Clinically, allodynia is well-documented as a common problem for neuropathic pain patients [145], and the von Frey test is a highly validated assessment tool for allodynia [17]. Several gene therapy vector approaches for neuropathic pain control are being pursued for directed delivery to the dorsal spinal cord & DRG (the pain compartments) & to specific cell types within those compartments, such as glial cells in the DRG (satellite & Schwann cells) or astrocytes and microglia in the dorsal horn of the spinal cord, with one recent clinical trial underway [84].
No report currently exits that directly links decreased IL-10 gene expression and neuropathic pain in humans. However, several reports have documented that gene polymorphisms of the anti-inflammatory cytokine, IL-10 that lead to decreased IL-10 expression are associated with the incidence of pain in inflammatory bowel disorders, neuropathic pain, and chronic pelvic pain [29, 61, 118]. In addition, several clinical studies document increased circulating IL-1β and TNF-α levels with concurrent decreased circulating IL-10 [132]. Further, pro-inflammatory cytokine polymorphisms have been correlated in chronic pelvic pain syndromes [118], and in patients with neuro-Behcet's disease; an inflammatory disorder with unknown etiology that produces painful immune-mediated meningioencephalitis [37].
Importantly, the potential application of IL10 is not necessarily intended to correct IL-10 function per se. Rather, IL-10 is promising for pathological pain treatment because it exerts powerful anti-inflammatory actions. In numerous animal models, pain mediated by proinflammatory cytokine actions on pain processing neurons is controlled by spinal IL-10 [97, 114]. Because TNF-α and IL-1 are so powerful, immune and glial cells have evolved the means to create negative feedback suppression of their activity. This is achieved via mechanisms that include the production of IL-10 [102]. While spinal cord neurons do not express receptors for nor make IL-10 [73], IL-10 terminates pro-inflammatory processes by inhibiting a variety of cytokines including TNF-α and IL-1β at multiple levels. IL-10 prevents p38 MAP kinase activation, NFkB activation, translocation & DNA binding; preventing TNF-α and IL-1β transcription, translation & post-translational processing; destabilizing TNF-α and IL-1β mRNA to decrease its half-life; desensitizing responses to TNF-α and IL-1β by increasing IL-1 receptor antagonist & TNF decoy receptors. A comprehensive suppression of TNF-α and IL-1β production and signaling can be achieved through the actions of IL-10. IL-10 is both a natural product of glia (astrocytes & microglia) and innate immune cells like macrophage and dendritic cells & binds to receptors expressed by them ([102] for review).
Prior work on the LFA-1 antagonist molecule, BIRT-377 and its derivatives, NorBIRT and DANBIRT, demonstrated that these small molecules exert antiproliferative and anti-migratory properties of leukocytes. Yet, whether BIRT-377, NorBIRT and DANBIRT act to directly inhibit IL-1β, TNF-α, CCL2 and NO actions in the spinal cord leading to suppression of pathological pain was heretofore unknown.
Better understanding of the aforementioned processes will help address the persistent problem of chronic neuropathic pain in the patient population.